Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome

Anne Legrand (1, 2) , Charline Guery (1) , Julie Faugeroux (1) , Erika Fontaine (1) , Carole Beugnon (1) , Amélie Gianfermi (1) , Irmine Loisel-Ferreira (1) , Marie-Christine Verpont (3) , Salma Adham (2) , Tristan Mirault (1, 2) , Juliette Hadchouel (3) , Xavier Jeunemaitre (2, 1)

1 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
2 HEGP - Hôpital Européen Georges Pompidou [APHP]
3 Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1 +/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1 +/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1 +/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

Domaines: Génétique animale

Anne Legrand, Charline Guery, Julie Faugeroux, Erika Fontaine, Carole Beugnon, et al.. Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome. PLoS Genetics, 2022, 18 (3), pp.e1010059. ⟨10.1371/journal.pgen.1010059⟩. ⟨hal-03671183⟩